Click-synthesized triazoles-phosphonium hybrids as CYP51-targeting antifungal agents against multidrug-resistant Candida spp.: Experimental and in silico evaluation

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Five previously reported 1,2,3-triazole-phosphonium hybrids (1a‑5a) were resynthesized via click chemistry and evaluated for their antifungal activity against multidrug‑resistant C. albicans and Candida glabrata. The compounds showed MIC values of 1.00-4.00 µg/mL against C. albicans and 1.00–2.00 µg/mL against C. glabrata. Compounds 2a and 5a showed lower MIC values against C. glabrata than voriconazole. In combination studies, several compounds acted as synergists or modulators with conventional antifungals (FICI ≤ 0.5-4.0), although antagonistic interactions with caspofungin were observed against certain C. glabrata clinical isolates (FICI > 4.0). The compounds also inhibited biofilm formation; compound 5a showed the lowest SMIC₅₀ (8 µg/mL). Molecular docking predicted strong binding to fungal CYP51 enzymes (binding energy: -9.5 to -12.6 kcal/mol) and comparatively weaker interactions with the human orthologue. These computational findings suggest a possible basis for selectivity, but this remains a hypothesis that requires experimental confirmation via enzymatic inhibition assays. In silico ADME predictions indicated favorable pharmacokinetic profiles, including high gastrointestinal absorption and bioavailability. Together, these results support further evaluation of triazole‑phosphonium hybrids as antifungal lead candidates, pending experimental target validation and cytotoxicity assessment.